tbuckley/cabot-search huggingface dataset:
R-Loop Accumulation in Spliceosome Mutant Leukemias Confers Sensitivity to PARP1 Inhibition by Triggering Transcription–Replication Conflicts
Authors: Zhiyan Silvia Liu, Sayantani Sinha, Maxwell Bannister, Axia Song, Erica Arriaga-Gomez, Alexander J. McKeeken, Elizabeth A. Bonner, Benjamin K. Hanson, Martina Sarchi, Kouhei Takashima, Dawei Zong, Victor M. Corral, Evan Nguyen, Jennifer Yoo, Wannasiri Chiraphapphaiboon, Cassandra Leibson, Matthew C. McMahon, Sumit Rai, Elizabeth M. Swisher, Zohar Sachs, Srinivas Chatla, Derek L. Stirewalt, H. Joachim Deeg, Tomasz Skorski, Eirini P. Papapetrou, Matthew J. Walter, Timothy A. Graubert, Sergei Doulatov, Stanley C. Lee, Hai Dang Nguyen
Journal: Cancer Research (2023)

Abstract RNA splicing factor (SF) gene mutations are commonly observed in patients with myeloid malignancies. Here we showed that SRSF2- and U2AF1-mutant leukemias are preferentially sensitive to PARP inhibitors (PARPi), despite being proficient in homologous recombination repair. Instead, SF-mutant leukemias exhibited R-loop accumulation that elicited an R-loop–associated PARP1 response, rendering cells dependent on PARP1 activity for survival. Consequently, PARPi induced DNA damage and cell death in SF-mutant leukemias in an R-loop-dependent manner. PARPi further increased aberrant R-loop levels, causing higher transcription–replication collisions and triggering ATR activation in SF-mutant leukemias. Ultimately, PARPi-induced DNA damage and cell death in SF-mutant leukemias could be enhanced by ATR inhibition. Finally, the level of PARP1 activity at R-loops correlated with PARPi sensitivity, suggesting that R-loop-associated PARP1 activity could be predictive of PARPi sensitivity in patients harboring SF gene mutations. This study highlights the potential of targeting different R-loop response pathways caused by spliceosome gene mutations as a therapeutic strategy for treating cancer. Significance: Spliceosome-mutant leukemias accumulate R-loops and require PARP1 to resolve transcription–replication conflicts and genomic instability, providing rationale to repurpose FDA-approved PARP inhibitors for patients carrying spliceosome gene mutations.
Impact of COVID‐19 on care‐seeking patterns for hay fever in Japan: A retrospective claims database cohort study
Authors: Yasutsugu Akasaki, Masao Iwagami, Jaemyoung Sung, Ken Nagino, Takeya Adachi, Hideaki Morita, Mayumi Tamari, Keigo Kainuma, Keiko Kan‐o, Hiroaki Ogata, Masafumi Sakashita, Masaki Futamura, Yosuke Kurashima, Saeko Nakajima, Katsunori Masaki, Yasushi Ogawa, Sakura Sato, Akihiro Miyagawa, Akie Midorikawa‐Inomata, Keiichi Fujimoto, Yuichi Okumura, Kenta Fujio, Tianxiang Huang, Kunihiko Hirosawa, Yuki Morooka, Shintaro Nakao, Akira Murakami, Hiroyuki Kobayashi, Takenori Inomata
Journal: Allergy (2023)

The data that support the findings of this study are available from the corresponding author upon reasonable request. Appendix S1 Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Pathologic Exploration of the Axillary Soft Tissue Microenvironment and Its Impact on Axillary Management and Breast Cancer Outcomes
Authors: George E. Naoum, Oluwadamilola Oladeru, Hazim Ababneh, Amy Shui, Amy Ly, Alphonse G. Taghian
Journal: Journal of Clinical Oncology (2023)

PURPOSE Axillary soft tissue (AXT) involvement with tumor cells extending beyond the positive lymph node (LN+) and extracapsular extension (ECE) has been overlooked in breast pathology specimen analysis. MATERIALS AND METHODS We analyzed 2,162 LN+ patients, dividing them into four groups on the basis of axillary pathology: (1) LN+ only, (2) LN+ and ECE only, (3) LN+ and AXT without ECE, and (4) LN+ with both AXT and ECE. The primary end points were 10-year locoregional failure (LRF), the 10-year axillary failure, and 10-year distant metastasis rates. Multivariable Cox models, accounting for clinical factors, were fitted using the entire cohort, and subgroups analyses were conducted. RESULTS The median follow-up was 9.4 years. The 10-year distant metastasis incidence was 42% for LN + AXT + ECE, 23% for both LN + AXT and LN + ECE only, and 13% for LN+ only. The 10-year axillary failure rates were 4.5% for LN + AXT + ECE, 4.6% for LN + AXT, 0.8% for LN + ECE only, and 1.6% for LN+ only. The 10-year LRF rates were 14% for LN + AXT + ECE, 10% for LN + AXT, 5.7% for LN + ECE only, and 6.2% for LN+ only. Multivariable analysis revealed that AXT was significantly associated with distant metastasis (hazard ratio [HR], 1.6; P &lt; .001), locoregional failure (HR, 2.3; P &lt; .001), and axillary failure (HR, 3.3; P = .003). Subgroup analyses showed that regional LN radiation (RLNR) improved locoregional tumor outcomes with AXT, ECE, or both (HR, 0.5; P = .03). Delivering ≤50 Gy to the axilla in the presence of AXT/ECE increased axillary failure (HR, 3.0; P = .04). Moreover, when delivering RLNR, axillary LN dissection could be de-escalated to sentinel node biopsy even in the presence of features such as AXT or ECE without significantly increasing any failure outcome: (HR, 1.0; P = .92) for LRF, (HR, 1.1; P = .94) axillary failure, and (HR, 0.4; P = .01) distant metastasis. CONCLUSION Routine reporting of axillary tissue involvement, beyond LNs and ECE, is crucial in predicting breast cancer outcomes. Ruling out the presence of AXT is imperative before any form of axillary de-escalation, especially RLNR omission.
Soft Tissue Sarcomas in Adolescents and Young Adults
Authors: Aaron R. Weiss, Douglas J. Harrison
Journal: Journal of Clinical Oncology (2023)

Soft tissue sarcomas (STS) represent a heterogeneous group of extraskeletal mesenchymal tumors that affect individuals throughout the entire age continuum. Despite this pervasive influence, key differences exist in the presentation of these sarcomas across varying age groups that have prevented a more uniform approach to management. Notably, rhabdomyosarcoma (RMS) is more common in children, while most nonrhabdomyosarcoma soft tissue sarcoma (NRSTS) subtypes are more prevalent in adults. Older patients with NRSTS appear to have more molecularly complex biology and often present with more advanced disease compared with children. Poorer outcome disparities are observed in older patients with RMS despite receiving similar treatment as younger patients. In this review, we highlight differences in epidemiology, biology, and management paradigms for pediatric and adult patients with STS and explore opportunities for a unified approach to enhance the care and outcomes within the AYA population.
Psychological Outcomes in Adolescent and Young Adult Cancer Survivors
Authors: Meghan E. McGrady, Victoria W. Willard, AnnaLynn M. Williams, Tara M. Brinkman
Journal: Journal of Clinical Oncology (2023)

The diagnosis of cancer during adolescent and young adulthood (AYA) may alter the development and psychological trajectory of survivors across their lifespan. The current review focuses broadly on emotional health, social functioning, health behaviors, and cancer-related cognitive impairment (CRCI) among AYA survivors. Overall, AYA survivors appear to be at elevated risk of emotional distress symptoms, mood and anxiety disorders, suicide, and mental health care service utilization compared with individuals without a cancer history. Difficulties with social relationships and reduced achievement of expected social outcomes including educational attainment and employment have been reported. Despite risk for health-related morbidities, including subsequent neoplasms, many AYA survivors do not engage in health behaviors at the recommended levels for physical activity, diet, or tobacco and alcohol use. Although CRCI has not been comprehensively characterized in this population, subgroups of AYA survivors appear to be at risk for experiencing CRCI, including survivors of central nervous system tumors, Hodgkin lymphoma, testicular, and breast cancer. Across each considered domain of psychological functioning, intervention efforts have largely focused on acceptability and feasibility with an increasing focus on e/mHealth approaches. Future research should include multiphase studies, including randomized controlled trials designed to evaluate intervention efficacy and effectiveness. It is imperative that psychological interventions consider the unique needs of AYA survivors by developmental stage and across multiple levels of influence (patient, support system, institution, and health care system).
Long-Term Follow-Up of the Response-Adapted Intergroup EORTC/LYSA/FIL H10 Trial for Localized Hodgkin Lymphoma
Authors: Massimo Federico, Catherine Fortpied, Yana Stepanishyna, Manuel Gotti, Richard van der Maazen, Caterina Cristinelli, Alessandro Re, Wouter Plattel, Julien Lazarovici, Francesco Merli, Lena Specht, Jean-Marc Schiano de Colella, Martin Hutchings, Annibale Versari, Véronique Edeline, Aspasia Stamatoulas, Theodore Girinsky, Umberto Ricardi, Berthe Aleman, Bart Meulemans, Sanne Tonino, John Raemaekers, Marc André
Journal: Journal of Clinical Oncology (2023)

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. The primary analysis of the Early positron emission tomography (ePET) Response–Adapted Treatment in localized Hodgkin Lymphoma H10 Trial demonstrated that in ePET-negative patients, the risk of relapse increased when involved-node radiotherapy (INRT) was omitted and that in ePET-positive patients, switching from doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) to bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPPesc) significantly improved 5-year progression-free survival (PFS). Here, we report the final results of a preplanned analysis at a 10-year follow-up. In the favorable (F) ePET-negative group, the 10-year PFS rates were 98.8% versus 85.4% (hazard ratio [HR], 13.2; 95% CI, 3.1 to 55.8; P value for noninferiority = .9735; difference test P &lt; .0001) in favor of ABVD + INRT; in the unfavorable (U) ePET-negative group, the 10-year PFS rates were 91.4% and 86.5% (HR, 1.52; 95% CI, 0.84 to 2.75; P value for noninferiority = .8577; difference test P = .1628). In ePET-positive patients, the difference in terms of PFS between standard ABVD and intensified BEACOPPesc was no longer statistically significant (HR, 0.67; 95% CI, 0.37 to 1.20; P = .1777). In conclusion, the present long-term analysis confirms that in ePET-negative patients, the omission of INRT is associated with lower 10-year PFS. Instead, in ePET-positive patients, no significant difference between standard and experimental arms emerged although intensification with BEACOPPesc was safe, with no increase in late adverse events, namely, second malignancies.
Blinatumomab for First-Line Treatment of Children and Young Persons With B-ALL
Authors: Angus Hodder, Avijeet K. Mishra, Amir Enshaei, Susan Baird, Kaljit Bhuller, Ismail Elbeshlawi, Denise Bonney, Katherine Clesham, Michelle Cummins, Aditi Vedi, Brenda Gibson, Lindsay George, Danielle Ingham, Galina Jigoulina, Donna Lancaster, Katherine Lindsay, Majid Madni, Andrea Malone, Bethany Mitchell, John Moppett, Jayashree Motwani, Anthony V. Moorman, Katharine Patrick, Lamia Samrin, Sanjay Tewari, Indu Thakur, David O'Connor, Sujith Samarasinghe, Ajay Vora
Journal: Journal of Clinical Oncology (2023)

PURPOSE We tested whether blinatumomab (Blina) is effective as a toxicity-sparing alternative to first-line intensive chemotherapy in children and young persons (CYP) with B-ALL who were chemotherapy-intolerant or chemotherapy-resistant. METHODS Data were collected for consecutive CYP (age 1-24 years) with Philadelphia chromosome–positive or Philadelphia chromosome–negative B-ALL who received Blina as first-line therapy. Blina was given as replacement for postremission intensive chemotherapy to patients with chemotherapy intolerance or resistance. Blina responders received further chemotherapy (Blin-CT) or first remission hematopoietic stem-cell transplant (Blin-HSCT) if indicated. Event-free survival (EFS) and overall survival (OS) of the Blin-CT group were compared with those of matched controls treated with standard chemotherapy in the UKALL 2003 trial. Events were defined as death, relapse, or secondary cancer. RESULTS From February 2018 to February 2023, 105 patients were treated, of whom 85 were in the Blin-CT group and 20 were in the Blin-HSCT group. A majority of Blin-CT patients received Blina for chemotherapy intolerance (70 of 85, 82%), and the group had a higher-risk profile than unselected patients with B-ALL. Blina was well tolerated with only one patient having a grade 3/4–related toxicity event, and of the 60 patients who were minimal residual disease–positive pre-Blina, 58 of 60 (97%) responded. At a median follow-up of 22 months, the 2-year outcomes of the 80 matched Blin-CT group patients were similar to those of 192 controls (EFS, 95% [95% CI, 85 to 98] v 90% [95% CI, 65 to 93] and OS, 97% [95% CI, 86 to 99] v 94% [95% CI, 89 to 96]). Of the 20 in the HSCT group, three died because of transplant complications and two relapsed. CONCLUSION Blina is safe and effective in first-line treatment of chemotherapy-intolerant CYP with ALL.
Acute heart failure: mechanisms and pre-clinical models—a Scientific Statement of the ESC Working Group on Myocardial Function
Authors: Michele Ciccarelli, Inês Falcão Pires, Johann Bauersachs, Luc Bertrand, Christophe Beauloye, Dana Dawson, Nazha Hamdani, Denise Hilfiker-Kleiner, Linda W van Laake, Frank Lezoualc’h, Wolfgang A Linke, Ida G Lunde, Peter P Rainer, Antonella Rispoli, Valeria Visco, Albino Carrizzo, Matteo Dal Ferro, Davide Stolfo, Jolanda van der Velden, Serena Zacchigna, Stephane Heymans, Thomas Thum, Carlo Gabriele Tocchetti
Journal: Cardiovascular Research (2023)

Abstract While chronic heart failure (CHF) treatment has considerably improved patient prognosis and survival, the therapeutic management of acute heart failure (AHF) has remained virtually unchanged in the last decades. This is partly due to the scarcity of pre-clinical models for the pathophysiological assessment and, consequently, the limited knowledge of molecular mechanisms involved in the different AHF phenotypes. This scientific statement outlines the different trajectories from acute to CHF originating from the interaction between aetiology, genetic and environmental factors, and comorbidities. Furthermore, we discuss the potential molecular targets capable of unveiling new therapeutic perspectives to improve the outcome of the acute phase and counteracting the evolution towards CHF.
Building a Better Silver Bullet: Current Status and Perspectives of Non‐Viral Vectors for mRNA Vaccines
Authors: Jiayu Gu, Zhourui Xu, Qiqi Liu, Shiqi Tang, Wenguang Zhang, Shouxia Xie, Xiaoyan Chen, Jiajie Chen, Ken‐Tye Yong, Chengbin Yang, Gaixia Xu
Journal: Advanced Healthcare Materials (2023)

Abstract In recent years, messenger RNA (mRNA) vaccines have exhibited great potential to replace conventional vaccines owing to their low risk of insertional mutagenesis, safety and efficacy, rapid and scalable production, and low‐cost manufacturing. With the great achievements of chemical modification and sequence optimization methods of mRNA, the key to the success of mRNA vaccines is strictly dependent on safe and efficient gene vectors. Among various delivery platforms, non‐viral mRNA vectors could represent perfect choices for future clinical translation regarding their safety, sufficient packaging capability, low immunogenicity, and versatility. In this review, the recent progress in the development of non‐viral mRNA vectors is focused on. Various organic vectors including lipid nanoparticles (LNPs), polymers, peptides, and exosomes for efficient mRNA delivery are presented and summarized. Furthermore, the latest advances in clinical trials of mRNA vaccines are described. Finally, the current challenges and future possibilities for the clinical translation of these promising mRNA vectors are also discussed.
Impact of Visit Volume on the Effectiveness of Electronic Tools to Improve Heart Failure Care
Authors: Amrita Mukhopadhyay, Harmony R. Reynolds, William C. King, Lawrence M. Phillips, Arielle R. Nagler, Adam Szerencsy, Archana Saxena, Nathan Klapheke, Stuart D. Katz, Leora I. Horwitz, Saul Blecker
Journal: JACC Heart Failure (2023)
Clinical applicability of the urticaria control test in patients with chronic urticaria: Further evidence from 622 adult and pediatric patients with different disease subtypes
Authors: Ditte Georgina Zhang, Jennifer Astrup Sørensen, Misbah Noshela Ghazanfar, Simon Francis Thomsen
Journal: Allergy (2023)

The data that support the findings of this study are available from the corresponding author upon reasonable request. Appendix Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Population mobility data provides meaningful indicators of fast food intake and diet-related diseases in diverse populations
Authors: Abigail L. Horn, Brooke M. Bell, Bernardo García Bulle Bueno, Mohsen Bahrami, Burçin Bozkaya, Yan Cui, John P. Wilson, Alex Pentland, Esteban Moro, Kayla de la Haye
Journal: npj Digital Medicine (2023)

Abstract The characteristics of food environments people are exposed to, such as the density of fast food (FF) outlets, can impact their diet and risk for diet-related chronic disease. Previous studies examining the relationship between food environments and nutritional health have produced mixed findings, potentially due to the predominant focus on static food environments around people’s homes. As smartphone ownership increases, large-scale data on human mobility (i.e., smartphone geolocations) represents a promising resource for studying dynamic food environments that people have access to and visit as they move throughout their day. This study investigates whether mobility data provides meaningful indicators of diet, measured as FF intake, and diet-related disease, evaluating its usefulness for food environment research. Using a mobility dataset consisting of 14.5 million visits to geolocated food outlets in Los Angeles County (LAC) across a representative sample of 243,644 anonymous and opted-in adult smartphone users in LAC, we construct measures of visits to FF outlets aggregated over users living in neighborhood. We find that the aggregated measures strongly and significantly correspond to self-reported FF intake, obesity, and diabetes in a diverse, representative sample of 8,036 LAC adults included in a population health survey carried out by the LAC Department of Public Health. Visits to FF outlets were a better predictor of individuals’ obesity and diabetes than their self-reported FF intake, controlling for other known risks. These findings suggest mobility data represents a valid tool to study people’s use of dynamic food environments and links to diet and health.
Tension-activated nanofiber patches delivering an anti-inflammatory drug improve repair in a goat intervertebral disc herniation model
Authors: Ana P. Peredo, Sarah E. Gullbrand, Chet S. Friday, Brianna S. Orozco, Bijan Dehghani, Austin C. Jenk, Edward D. Bonnevie, Rachel L. Hilliard, Hannah M. Zlotnick, George R. Dodge, Daeyeon Lee, Julie B. Engiles, Michael W. Hast, Thomas P. Schaer, Harvey E. Smith, Robert L. Mauck
Journal: Science Translational Medicine (2023)

Conventional microdiscectomy treatment for intervertebral disc herniation alleviates pain but does not repair the annulus fibrosus, resulting in a high incidence of recurrent herniation and persistent dysfunction. The lack of repair and the acute inflammation that arise after injury can further compromise the disc and result in disc-wide degeneration in the long term. To address this clinical need, we developed tension-activated repair patches (TARPs) for annulus fibrosus repair and local delivery of the anti-inflammatory factor anakinra (a recombinant interleukin-1 receptor antagonist). TARPs transmit physiologic strain to mechanically activated microcapsules embedded within the patch, which release encapsulated bioactive molecules in direct response to spinal loading. Mechanically activated microcapsules carrying anakinra were loaded into TARPs, and the effects of TARP-mediated annular repair and anakinra delivery were evaluated in a goat model of annular injury in the cervical spine. TARPs integrated with native tissue and provided structural reinforcement at the injury site that prevented aberrant disc-wide remodeling resulting from detensioning of the annular fibrosus. The delivery of anakinra by TARP implantation increased matrix deposition and retention at the injury site and improved maintenance of disc extracellular matrix. Anakinra delivery additionally attenuated the inflammatory response associated with TARP implantation, decreasing osteolysis in adjacent vertebrae and preserving disc cellularity and matrix organization throughout the annulus fibrosus. These results demonstrate the therapeutic potential of TARPs for the treatment of intervertebral disc herniation.
Identification of a small-molecule Tim-3 inhibitor to potentiate T cell–mediated antitumor immunotherapy in preclinical mouse models
Authors: Shuaiya Ma, Ye Tian, Jiali Peng, Chaojia Chen, Xueqi Peng, Fabao Zhao, Zhenyu Li, Mengzhen Li, Fangcheng Zhao, Xue Sheng, Runzhe Zong, Yiquan Li, Jiwei Zhang, Mingyan Yu, Qingfen Zhu, Xiaoyu Tian, Yuyang Li, Markus R. Neckenig, Huiqing Liu, Peng Zhan, Xuetian Yue, Zhuanchang Wu, Lifen Gao, Xiaohong Liang, Xinyong Liu, Chunyang Li, Chunhong Ma
Journal: Science Translational Medicine (2023)

T cell immunoglobulin and mucin-containing molecule 3 (Tim-3), expressed in dysfunctional and exhausted T cells, has been widely acknowledged as a promising immune checkpoint target for tumor immunotherapy. Here, using a strategy combining virtual and functional screening, we identified a compound named ML-T7 that targets the FG-CC′ cleft of Tim-3, a highly conserved binding site of phosphatidylserine (PtdSer) and carcinoembryonic antigen–related cell adhesion molecule 1 (CEACAM1). ML-T7 enhanced the survival and antitumor activity of primary CD8 + cytotoxic T lymphocytes (CTLs) and human chimeric antigen receptor (CAR) T cells and reduced their exhaustion in vitro and in vivo. In addition, ML-T7 promoted NK cells’ killing activity and DC antigen-presenting capacity, consistent with the reported activity of Tim-3. ML-T7 strengthened DCs’ functions through both Tim-3 and Tim-4, which is consistent with the fact that Tim-4 contains a similar FG-CC′ loop. Intraperitoneal dosing of ML-T7 showed comparable tumor inhibitory effects to the Tim-3 blocking antibody. ML-T7 reduced syngeneic tumor progression in both wild-type and Tim-3 humanized mice and alleviated the immunosuppressive microenvironment. Furthermore, combined ML-T7 and anti–PD-1 therapy had greater therapeutic efficacy than monotherapy in mice, supporting further development of ML-T7 for tumor immunotherapy. Our study demonstrates a potential small molecule for selectively blocking Tim-3 and warrants further study.